Overall Summary The central nervous system (CNS) plays a major role in obesity and hypertension but the knowledge of the neural circuits controlling physiological pathways regulating blood pressure, feeding, and energy expenditure remain limited. The long term goal and central theme of the third competitive renewal of this program is to identify mechanisms and neural circuitry regulating blood pressure and energy homeostasis in hypertension and common obesity. Many of these mechanisms are shared among blood pressure and metabolic neural control circuits but differentially control physiological endpoints by virtue of their location in the CNS and the cellular pathways engaged. We will examine molecular mechanisms operating in the forebrain and hypothalamus which alter the hypertensive response to cardiovascular and metabolic stressors, the mechanisms regulating renin-angiotensin system (RAS) activity and its relationship with arterial pressure and metabolic function, mechanisms regulating the trafficking and function of critical receptors regulating cardiovascular and metabolic functions, and the intracellular signals that differentially control resting metabolic rate and arterial pressure. Project 1 will test the hypothesis that forebrain leptin receptors and microglial activation in the neural network controlling sympathetic tone and body energy metabolism play a fundamental role in sensitization of the hypertensive response which is mediated by activation of N-Methyl-D-aspartate receptors. Project 2 will test the hypotheses that the coordinated expression of renin-a and renin-b in the subfornical organ (SFO), paraventricular nucleus (PVN), and arcuate nucleus (ARC) mediates local angiotensin-II (ANG) production and action to control autonomic output and thus cardiovascular and metabolic endpoints; and that disinhibition of renin-a expression with concomitant inhibition of renin-b expression in the SFO, PVN and ARC is required to mediate sensitization of the hypertensive response to mild humoral and dietary stressors. Project 3 will test the hypotheses that dysfunction a protein complex, the BBSome, in the contributes to common diet-induced obesity and to obesity-associated hypertension and sympathetic nerve activation by a) altering the cellular processes underling the trafficking of the receptors that regulate energy homeostasis and blood pressure, and b) by interfering with the firing activity of ARC proopiomelanocortin neurons. Project 4 will test the hypothesis that ANG acts at AT1 receptors on AgRP neurons of the ARC to activate a regulator of G-protein signaling-2 (RGS2)-sensitive G?i second-messenger cascade, which controls AgRP production and thus modulates melanocortin signaling, ultimately to control thermogenic SNA and resting metabolism. These projects are synergistic both conceptually and technically and will collectively advance our understanding of the basic molecular and cellular that underlie neural control of cardiovascular and metabolic functions in health and disease. Insights gained from our integrated proposed program can pave the way for novel therapeutic approaches for the treatment of to hypertension and obesity.